Medicament dispenser

ABSTRACT

There is provided a medicament dispenser comprising a body, a medicament container and reset means for resetting a mechanical mechanism after actuation thereof, wherein the reset means comprises a reset coupling. The coupling is reversibly deformable in response to the application of non-mechanical energy thereto. The non-mechanical energy may comprise heat energy, electrical current energy, electrical field energy or magnetic field energy.

This application is filed pursuant to 35 USC 371 as a U.S. NationalPhase Application of Ser. No. PCT/EP00/12390 filed 8 Dec. 2000, whichclaims priority from GB 9929281.5 filed 11 Dec. 1999; GB 0004359.6 filed25 Feb. 2000; GB 0011124.5 filed 10 May 2000; and GB 0026648.6 filed 31Oct. 2000, all in the United Kingdom.

This invention relates to a medicament dispenser having reset means forresetting a mechanical mechanism of the dispenser after actuationthereof. The dispenser is particularly suitable for use as an inhalationdevice.

It is well known to treat patients with medicaments contained in anaerosol, for example, in the treatment of respiratory disorders. It isalso known to use for such treatment, medicaments which are contained inan aerosol and are administered to a patient by means of an inhalationdevice comprising a tubular housing or sleeve in which the aerosolcontainer is located and an outlet tube leading out of the tubularhousing. Such inhalation devices are generally referred to as metereddose inhalers (MDIs). The aerosol containers used in such inhalationdevices are designed to deliver a predetermined dose of medicament uponeach actuation by means of an outlet valve member at one end which canbe opened either by depressing the valve member while the container isheld stationary or by depressing the container while the valve member isheld stationary. In the use of such devices, the aerosol container isplaced in the tubular housing with the outlet valve member of thecontainer communicating via a support with the outlet tube, for examplea nozzle or mouthpiece. When used for dispensing medicaments, forexample in bronchodilation therapy, the patient then holds the housingin a more or less upright condition and the mouthpiece or nozzle of theinhalation device is placed in the mouth or nose of the patient. Theaerosol container is pressed towards the support to dispense a dose ofmedicament from the container which is then inhaled by the patient.

It is also known to use dry powder inhalation devices for the deliveryof inhalable medicament. In one aspect, such dispensers comprisepre-metered doses of powdered medicament, for example in capsules orblisters. In another aspect, such dispensers comprise a reservoir ofpowdered medicament from which doses are metered prior to or concurrentwith the delivery process. In either case, the device may be designedfor passive release of medicament, where the medicament is simply madeavailable at a delivery position for aerosolisation in response to theinhalation of the patient. Alternatively, an active release mechanismmay be used whereby a ‘puff’ of compressed gas or air is provided to thedelivery position to assist in aerosolisation of the powder prior to orconcurrent with the inhalation of the patient. Such devices aregenerally called active release dry powder inhalers (active DPIs). Thesource of the compressed gas or air is generally an aerosol container.

It is also well known to use syringes for the delivery of injectablemedicament to a patient. Traditional syringes rely on puncturing of thepatient's skin by a hollow needle through which the injectablemedicament (in solution or suspension form) is delivered to the muscleor tissue of the patient. Recently developed needleless systems for thedelivery of injectables employ high velocity injection of particleformulated drugs or vaccine through the skin and into any physicallyaccessible tissue. Other needleless systems employ similar high velocityinjection of drug or vaccine coated on to a suitable carrier particle.Such needleless systems may be configured to include a source ofcompressed air or gas, which on release provides energy to propel themedicament particles for injection into the skin.

It may be understood that effective delivery of medicament to thepatient using an inhalation device such as an MDI or active DPI asdescribed above is to an extent dependent on the patient's ability tomanually actuate the device (e.g. firing of the aerosol and/or resettingof the device) and to co-ordinate the actuation thereof with the takingof a sufficiently strong inward breath. For some patients, particularlyyoung children, the elderly and the arthritic, manual actuation of thedevice can present difficulties. Other patients find it difficult toco-ordinate the taking of a reliable inward breath with actuation of thedevice. Both of these sets of patients run the risk that they do notreceive the appropriate dose of medicament.

It may also be understood that effective delivery of medicament to thepatient using a syringe or needleless injection system as describedabove also requires care and dexterity.

The Applicants have now developed a medicament dispenser whichincorporates a reset mechanism which may not require manual actuation bythe patient. The advantages of having a positive reset mechanism arenumerous. In devices where there is no reset mechanism it is possiblefor the canister to stick in the firing position. This may effect theefficacy of further inhaler actuations as well as dosing efficacy.Furthermore, the longer the canister remains in the firing position, theincreased likelihood of medicament deposition and/or increasedmedicament concentration in the lower parts of the canister. A positivereset mechanism is therefore technically advantageous in addition toincreasing consumer confidence and ease of use of the device.

Actuation of the reset mechanism is responsive to the application ofnon-mechanical energy to a coupling element of the reset means. Thenon-mechanical energy can be in the form of heat provided by electricalcurrent flow through the coupling element, which in turn can be providedin response to the sensing of the breath of a patient. Alternatively,the non-mechanical energy can be in the form of a magnetic fieldprovided by a suitable magnetic field source such as a permanent magnetor an electromagnet.

U.S. Pat. No. 5,061,914 describes a shape memory alloy micro-actuator.The actuator comprises a nickel-titanium alloy material which undergoesa temperature induced phase transition when heated. The phase transitionresults in contraction of the actuator. The actuator can be mechanicallycoupled to a micro-mechanical element for motion thereof.

U.S. Pat. No. 5,958,154 describes alloy materials which undergo a phasetransition in response to the application of a magnetic field.

Accordingly, in one aspect the invention provides a medicament dispensercomprising a body, a medicament container and reset means for resettinga mechanical mechanism after actuation thereof, wherein the reset meanscomprises a reset coupling which is reversibly deformable in response tothe application of non-mechanical energy thereto.

The mechanical mechanism may be selected from one or more of thefollowing:

(i) trigger means;

(ii) dose-metering means;

(iii) transport means;

(iv) dose-liberating means;

(v) exit channel-exposing means.

In one embodiment, the trigger means directly or indirectly actuates thedose-liberating means.

As used herein, the term dose-liberating means refers to any meansassociated with the dispenser for making a dose of medicament availableto a patient, for example, a dose-metering valve in an aerosol containerof medicament, means to aerosolize a dose of dry powder medicament,means to uncover or open a sealed capsule of pre-metered dry powdermedicament, or means to pump a dose of medicament for receipt by apatient. Thus, the dose-liberating means may take the form of a valve,and/or dose-metering means, and/or aerosolization means, and/orcontainer-opening means, and/or a pump (e.g. an aqueous pump), and/or aplunger (e.g. as in an automated syringe).

Suitably, the valve is a slide valve. Other valve systems include, butare not limited to, poppet valve systems, wedge gate valve systems,double-disc gate valve systems, globe and angle valve systems, swingcheck valve systems, end cock valve systems, and other like valvesystems. The valve design is typically a function of providing apredetermined dosage or amount of the medicament contained within thecontainer to a user.

Where the medicament container is a pressurized aerosol container, thevalve typically comprises a valve body having an inlet port throughwhich a medicament aerosol formulation may enter said valve body, anoutlet port through which the aerosol may exit the valve body and anopen/close mechanism by means of which flow through said outlet port iscontrollable.

The valve may be a slide valve wherein the open/close mechanismcomprises a sealing ring and receivable by the sealing ring a valve stemhaving a dispensing passage, the valve stem being slidably movablewithin the ring from a valve-closed to a valve-open position in whichthe interior of the valve body is in communication with the exterior ofthe valve body via the dispensing passage.

Typically, the valve is a metering valve. The metering volumes aretypically from 10 to 100 μl, such as 25 μl, 50 μl or 63 μl. Suitably,the valve body defines a metering chamber for metering an amount ofmedicament formulation and an open/close mechanism by means of which theflow through the inlet port to the metering chamber is controllable.Preferably, the valve body has a sampling chamber in communication withthe metering chamber via a second inlet port, said inlet port beingcontrollable by means of an open/close mechanism thereby regulating theflow of medicament formulation into the metering chamber.

The valve may also comprise a ‘free flow aerosol valve’ having a chamberand a valve stem extending into the chamber and movable relative to thechamber between dispensing and non-dispensing positions. The valve stemhas a configuration and the chamber has an internal configuration suchthat a metered volume is defined therebetween and such that duringmovement between is non-dispensing and dispensing positions the valvestem sequentially: (i) allows free flow of aerosol formulation into thechamber, (ii) defines a closed metered volume for pressurized aerosolformulation between the external surface of the valve stem and internalsurface of the chamber, and (iii) moves with the closed metered volumewithin the chamber without decreasing the volume of the closed meteredvolume until the metered volume communicates with an outlet passagethereby allowing dispensing of the metered volume of pressurized aerosolformulation. A valve of this type is described in U.S. Pat. No.5,772,085.

The valve may also have a structure and action similar to those aerosolvalves described in European Patent Application No. EP-A-870,699 and PCTPatent Application No. WO99/36334.

The pump may comprise a pump mechanism such as might be found in adispenser for dispensing liquid or solution (e.g. aqueous solution) formmedicament. The pump may deliver the medicament directly to the patient(e.g. as a nasal spray) or the pump may deliver the medicament to anintermediate position at which further energy is supplied thereto tofurther propel, aerosolize or otherwise direct the medicament dose tothe patient.

The dose-liberating means may comprise multiple plungers and multiplesyringe chambers. The syringe contents may for example, be liquid,solutions, suspensions, particulates or in freeze-dried form. A retractor reset mechanism is typically provided for the plunger.

Traditional syringes rely on puncturing of the patient's skin by ahollow needle through which the injectable medicament (in solution orsuspension form) is delivered to the muscle or tissue of the patient.Recently developed neeedleless systems for the delivery of injectablesemploy high velocity injection of particle formulated drugs or vaccinethrough the skin and into any physically accessible tissue. Otherneedleless systems employ similar high velocity injection of drug orvaccine coated onto a suitable carrier.

The dose-metering means may comprise a weight and/or a volume and/or atime and/or a surface-area regulated mechanism.

In one embodiment the dose-metering means may comprise a valve asdescribed hereinabove (for example, a linear or rotary valve) and/or apiston and/or a load cell and/or a plunger.

Preferably, the dose-metering means comprises at least one meteringchamber.

On actuation of the dose-metering means, the or each metering chambermay move into fluid communication with the reservoir.

Alternatively, or in addition, the dose-metering means and the reservoirmay be relatively rotatable with respect to each other about a commoncentral axis.

In one embodiment the or each metering chamber is adapted to be in fluidcommunication selectively with the reservoir or with the patient.

The or each metering chamber may have a variable volume.

The or each metering chamber may have a fixed volume which meteringvolume is variable by insertion of a plunger or piston.

The or each metering chamber may be formed from expandable material.

The or each metering chamber may have a telescopic or concertinaarrangement.

In one embodiment, there may be a gas permeable dry powder retainingmeans below the or each metering chamber. The retaining means may bemade from a gas-permeable filter, a mesh screen, a porous material or aperforated chamber element.

The aerosolization means may comprise a container of compressed gas(e.g. an inert gas or air), or a liquefied propellant under pressure.

The aerosolization means may comprise means to propel pressurised gasthrough a metered dose. The gas-propelling means may provide at leastone pulse of gas on actuation. The gas-propelling means provides onepulse of gas for each dose dispensed. The gas may be air or an inertgas.

In one embodiment, the medicament dispenser may be in the form of anactive dry powder inhaler in which a “puff” of compressed air or gas(e.g. helium) is delivered from the aerosolisation means, such as anaerosol container, to aerosolize a dose of released dry powdermedicament.

In another embodiment, the medicament dispenser is in the form of aneedleless injection system in which compressed air or gas (e.g. helium)is delivered at high velocity from the aerosol container to propel adose of dry powder medicament for injection into the skin.

Thus, suitably the aerosol container, which as used herein refers to anysuitable container for comprising liquefied gas under pressure,comprises a compressed air or gas (e.g. helium).

In another aspect, the medicament container may be arranged for rupturein response to firing of the aerosolisation means.

In one embodiment, the medicament is pre-metered prior to actuation ofthe dispenser by the patient, for example, the medicament is pre-meteredin capsules, strip or tape form.

The container-opening means may liberate the medicament from themedicament container for receipt by a patient.

The aerosolization means may liberate a pre-metered dose of medicamentfor receipt by a patient.

The transport means may transport an amount of medicament from a restposition to a delivery position. In one embodiment, the transport meansmay take the form of a perforated strip and claw advancement mechanism.In another embodiment, the transport means may take the form of aratchet wheel and a driving pawl advancement mechanism.

As used herein the term exit channel refers to a channel for passage ofthe medicament to a patient after the dispenser is actuated, and mayinclude a mouthpiece or nosepiece or skin-contacting or skin-penetratingchannel. The exit channel exposing means may either comprise areplaceable cover/lid/membrane for protecting an exit channel of thedispenser, or refer to means for directly or indirectly exposing theexit channel prior to use by a patient.

The term ‘non-mechanical energy’ herein is used to mean essentially anyenergy type which is not mechanical energy. The coupling and any resetcoupling herein typically comprise a material which deforms, orundergoes a phase transition in response to the application ofnon-mechanical energy, thereby resulting in a change in shape/dimensionof the coupling which serves to actuate the reset means. In embodimentsthe energy may be in the form of heat energy, electrical current energy,electrical field energy and magnetic field energy.

Preferably, the non-mechanical energy comprises electric current flowthrough the coupling or reset coupling.

Preferably, the coupling or reset coupling comprises a wire, strip, coilor tube.

Arrangements comprising multiple strips, wires, coils, or tubes are alsoenvisaged. The multiple strips, wires, coils, or tubes may be arrangedin any suitable fashion including parallel or series arrangements andbundle arrangements.

The coupling may be coated with any suitable coating, or encased withinany suitable encasing including a shrink-wrap sheath.

In one particular aspect, the coupling or reset coupling comprises oneor more wires which contract in response to application ofnon-mechanical energy thereto.

Preferably, the degree of contraction of the coupling is from 2% to 8%.

In embodiments, the coupling comprises an alloy which undergoes a phasetransition on heating (shape memory alloys). Certain shape memory alloysalso undergo a change in shape on recooling without externally appliedenergy. Such two way shape memory alloys are also envisaged for useherein.

In one embodiment, the shape memory alloy is preferably anickel-titanium alloy such as a nickel-titanium alloy comprising from 5%to 95%, preferably from 20% to 80%, nickel by weight and from 95% to 5%,preferably from 80% to 20%, titanium by weight. By nickel-titanium alloyit is meant an alloy comprised essentially of nickel and titanium,although other elements such as Cu and Nb may be present in small (e.g.trace) amounts.

In other embodiments, the shape memory alloy is preferably acopper-aluminium-nickel alloy or a copper-zinc-aluminium alloy. Traceamounts of other elements may also be present.

In further embodiments, the coupling comprises an alloy which undergoesa phase transition on application of a magnetic field thereto (magneticshape memory alloys). These materials are generally intermetallic,ferromagnetic alloys that exhibit twin variants in the martensitic, orlow-temperature, phase of the material. Suitable magnetic shape memoryalloys are for example, described in U.S. Pat. No. 5,958,154.

In one embodiment, the magnetic shape memory alloy exhibits anaustenitic crystal structure above a characteristic phase transformationtemperature and also exhibits a martensitic twinned crystal structurebelow the phase transformation temperature. The alloy has amagnetocrystalline anisotropy energy that is sufficient to enable motionof twin boundaries of the martensitic twinned crystal structure inresponse to application of a magnetic field to the martensitic twinnedcrystal structure.

Where a magnetic shape memory alloy is employed the medicament dispenserpreferably includes a magnetic field source disposed with respect to thecoupling in an orientation that applies to the coupling a magneticactuation field in a direction that is substantially parallel with aselected twin boundary direction of the martensitic twinned crystalstructure of the coupling material.

Alternatively, the medicament dispenser preferably includes a magneticbias field source disposed with respect to the coupling in anorientation that applies a magnetic bias field to the coupling, and amagnetic actuation field source disposed with respect to the coupling inan orientation that applies a magnetic actuation field to the couplingmaterial in a direction that is substantially perpendicular to theorientation of the applied magnetic bias field.

A preferred magnetic shape memory alloy is the actuator materialcomprising an alloy composition defined as Ni_(65-x-y)Mn₂₀+xGa₁₅+y,where x is between 3 atomic % and 15 atomic % and y is between 3 atomic% and 12 atomic %. Preferably, the actuator material comprises an alloycomposition defined as Ni_(65-x-y)Mn₂₀+xGa₁₅+y, where x is between 6atomic % and 10 atomic % and y is between 5 atomic % and 9 atomic %; orwhere x is between 12 atomic % and 15 atomic % and y is between 3 atomic% and 6 atomic %; or where x is between 10 atomic % and 14 atomic % andy is between 3 atomic % and 6 atomic %; or where x is between 7 atomic %and 11 atomic % and y is between 3 atomic % and 7 atomic %. In aparticularly preferred aspect, the alloy is Ni₅₀Mn₂₅Ga₂₅.

Another preferred magnetic shape memory alloy is the alloy having thecomposition(Ni_(a)Fe_(b)Co_(c))_(65-x-y)(Mn_(d)Fe_(e)Co_(f))₂₀+x(Ga_(g)Si_(h)Al_(i))₁₅+y,where x is between 3 atomic % and 15 atomic % and y is between 3 atomic% and 12 atomic %, and where a+b+c=1, where d+e+f=1, and g+h+i=1.

In preferred aspects, b is between zero and 0.6, c is between zero and0.6, and e,f,h and i are each zero; or b and c are each zero, e isbetween zero and 0.6, f is between zero and 0.6, and h and i are eachzero; or b, c, e and f are each zero, h is between zero and 0.5, and iis between zero and 0.5.

Other suitable shape memory alloys include those based on ion-exchangepolymer composites such as are described in ‘Ionic Polymer-MetalComposites (IPMC) As Biomimetic Sensors, Actuators & ArtificialMuscles—A Review’, M. Shahinpoor, Y. Bar-Cohen, J. O. Simpson and J.Smith as published at http://www.unm.edu/˜amri/paper.html.

Other potentially suitable shape memory alloys include those based oncontractile polymers such as are described in ‘Review of ArtificialMuscle based on Contractile Polymers’, Massachusetts Institute ofTechnology Artificial Intelligence Laboratory Memo No. 1330, November1991, David L. Brock.

Preferably, the one or more wires have a diameter from 30 to 400micrometers, preferably from 50 to 150 micrometers.

Preferably, the coupling comprises from two to twenty, preferably six totwelve wires which contract in response to the application ofnon-mechanical energy thereto. The wires may be arranged in any suitablefashion including parallel or series arrangements and bundlearrangements.

In another aspect, the coupling comprises a strip which comprisesmultiple layers of different metals. Suitable strips typically comprisea plurality of layers of material, each material having a differentcoefficient of thermal expansion.

Preferred examples of strips include those comprising multiple layers ofdifferent metals (e.g. bimetallic strips) and strips comprising at leastone piezoelectric material. Suitable piezoelectric materials includepiezoelectric ceramics, such as compounds of lead zirconate and leadtitanate, and piezoelectric crystals which are generally polycrystallineferroelectric materials with the perovskite structure. Suchpiezoelectric materials generally deform in response to the applicationof an electric field.

In one aspect, the coupling is deformable in response to heating arisingfrom electrical current flow in the range from 0.01A to 100A, preferablyfrom 0.1A to 5A.

In another aspect, the coupling is deformable in response to theapplication of an electrical field, particularly where the couplingcomprises a piezoelectric material.

In a further aspect, the coupling is deformable in response to amagnetic field of from 0.01 to 100 Tesla. The magnetic field may forexample, be produced by a permanent magnet or by an electromagnet.

Preferably, the medicament dispenser additionally comprises anelectrical energy source for providing electric current, or forproviding an electric field, or for powering an electromagnet to providea magnetic field. In one aspect, the electrical energy source comprisesa voltaic cell or battery of voltaic cells which may be rechargeable. Inanother aspect, the electrical energy source comprises a photovoltaiccell or battery of photovoltaic cells. In a further aspect, theelectrical energy source comprises a converter for converting mechanicalenergy into electrical energy. In a further aspect, the electricalenergy source comprises a capacitor for local storage of charge.Suitable capacitors comprise those known as ‘super capacitors’ with ahigh capacitance to size ratio, such as those consisting of solidelectrodes and liquid electrolyte.

Any known systems for power management and conservation may be employedwith the electrical energy source to manage and/or conserve the poweroutput thereof.

Energy may be conserved by a variety of means to enable the device tooperate for longer on a given source of energy, such as a battery.Energy conservation or saving methods have additional advantages interms of reducing the size requirements of the power source (e.g.battery) and thus the weight and portability of the inhalation device.

A variety of energy saving methods are available which generally involvereducing power consumption. One such method is to use a clock or timercircuit to switch the power on and off at regular or predeterminedintervals. In another method the system can selectively switch on/offspecific electronic devices, such as visual display units or sensors, inorder to power these devices only when they are required to perform aparticular sequence of events. Thus different electronic devices may beswitched on and off at varying intervals and for varying periods undercontrol of the system. The power sequencing system may also respond to asensor, such as a motion or breath sensor, which is activated on use ofthe device.

Low power or “micropower” components should be used within theelectronics where possible and if a high power device is required for aparticular function this should be put into a low power standby mode orswitched off when not required. Similar considerations apply in theselection of transducers.

Operation at low voltage is desirable since power dissipation generallyincreases with voltage.

For low power digital applications complementary metal oxidesemi-conductor (CMOS) devices are generally preferred and these may bespecially selected by screening for low quiescent currents. Clock speedsof processors and other logic circuits should be reduced to the minimumrequired for computational throughput as power consumption increaseswith frequency. Supply voltages should also be kept at minimal valuesconsistent with reliable operation because power dissipation in charginginternal capacitance's during switching is proportional to the square ofthe voltage. Where possible, supply voltages should be approximately thesame throughout the circuit to prevent current flowing through inputprotection circuits. Logic inputs should not be left floating andcircuits should be arranged so that power consumption is minimised inthe most usual logic output state. Slow logic transitions areundesirable because they can result in relatively large class-A currentsflowing. Resistors may be incorporated in the power supply to individualdevices in order to minimise current in the event of failure.

In some control applications, devices that switch between on and offstates are preferred to those that allow analog (e.g. linear) controlbecause less power is dissipated in low resistance on states and lowcurrent off states. Where linear components are used (e.g. certain typesof voltage regulators) then types with low quiescent currents should beselected. In some circuit configurations it is preferable to useappropriate reactive components (i.e. inductors and capacitors) toreduce power dissipation in resistive components.

Any electrical circuit may incorporate voltage amplification means forgenerating a higher voltage than that supplied by the voltaic cell orbattery of voltaic cells, for example a step-up or inverting switchingcircuit or a dc-dc converter incorporating an oscillator, transformerand rectifier.

The electrical circuit may incorporate one or more energy storagecomponents such as capacitors or inductors in order to supply a highenough instantaneous current to raise the temperature of the strips orwires at the required rate to the required temperature.

The input to the electrical circuit may be connected to the electricalenergy source by means of a mechanical, electro-mechanical or electronicswitching component.

The output of the electrical circuit may be connected to the strips orwires or to an electromagnet by means of a mechanical,electro-mechanical or electronic switching component or by a componentallowing the output current to be controlled in a linear or digital(e.g. pulse width modulated) manner.

Suitable control profiles (e.g. via pulse width modulation) includethose where the temperature of a shape memory alloy coupling isinitially raised to a holding temperature (H) which is just below thetransition temperature (T). Actuation of the coupling is then achievableby heating the coupling to a temperature (A) just above the transitiontemperature. This can be achieved rapidly because the holdingtemperature (H) is close to the transition temperature (T). When thesource of heating is switched off, deactuation also occurs rapidlybecause the cooling from a temperature (A) only just above thetransition temperature (T) to the transition temperature involves only asmall temperature decrease.

The strip or wire components may be powered from the battery using aswitching component without additional power supply circuitry.

Suitably, the medicament dispenser additionally comprises a controllerfor controlling the amount of electrical current flow through thecoupling or to an electromagnet.

Suitably, the medicament dispenser additionally comprises a timer forcontrolling the duration of electrical current flow through the couplingor to an electromagnet.

Suitably, the medicament dispenser additionally comprises a localelectrical source such as a capacitor or inductor.

The additional energy source may be mechanically generated, for example,the energy source may comprise a biasable resilient member e.g. aspring. Alternatively, the energy source may comprise a source ofcompressed fluid, preferably compressed gas. The energy source maycomprise a chemical energy source or a physically explosive energysource.

Preferably, deformation of the coupling and hence, actuation of thereset means is responsive to a patient-actuable mechanism.

In one aspect, said mechanism comprises a button, switch or leverarrangement.

In another aspect, the medicament dispenser is in the form of an inhalerfor the delivery of inhalable medicament. Preferably, deformation of thecoupling and hence, actuation of the reset means is responsive to apatient-actuable mechanism comprising a sensor which senses the breathof a patient. The deformation of the coupling (e.g. by electricalcurrent flow therethrough) may be responsive to the detection of theinward breath of a patient. Alternatively, deformation of the coupling(e.g. by electrical current flow therethrough) may be responsive to amechanism coupled to any point in the breathing pattern of the patient,such as the end of the outward breath.

In one aspect, the sensor comprises a breath-movable element which ismovable in response to the breath of a patient. Preferably, thebreath-movable element is selected from the group consisting of a vane,a sail, a piston, a diaphragm and an impeller.

Movement of the breath-movable element may be detectable by any suitabletechnique for detecting movement. Suitable techniques include opticaldetectors, magnetic detectors or detectors using detection ofcapacitative effects.

Optical detectors may be used to detect movement of the breath-movableelement by providing the element with a patterned outer surface, forexample strips in a barcode type arrangement, and locating the opticaldetector so that it points towards the patterned surface. Movement ofthe breath-movable element alters the amount of the light source whichreflects back onto the optical detector as the beam passes over thepatterned surface. The strips may be arranged so that the direction ofmovement of the element can be detected.

Magnetic detectors may be used to detect the movement of breath-movableelement by the use of a magnetic switch device. A reader is located onthe dispenser and magnetic material embedded within the breath-movableelement (or vice-versa). Movement of the breath-movable element resultsin a change of the magnetic field experienced by the reader.Alternatively, a Hall effect device can be used whereby a semiconductormeasures the strength of the magnetic field of the magnetic material onthe breath-movable element.

Detection of capacitative effects may be used to detect movement of thebreath-movable element by adding a conductive part to the element andalso to a second fixed part of the dispenser. Movement of thebreath-movable element results in a change in capacitance which can bemeasured.

In another aspect, the sensor comprises a pressure sensor for sensingthe pressure profile associated with the breath of a patient. A pressuretransducer is an example of a suitable pressure sensor.

In another aspect, the sensor comprises an airflow sensor for sensingthe airflow profile associated with the breath of a patient.

In another aspect, the sensor comprises a temperature sensor for sensingthe temperature profile associated with the breath of a patient.

In another aspect, the sensor comprises a moisture sensor for sensingthe moisture profile associated with the breath of a patient.

In another aspect, the sensor comprises a gas sensor for sensing theoxygen or carbon dioxide profile associated with the breath of apatient. The chemical profile of the inhaled and exhaled part of thebreath cycle varies and this further may be used as a measurement tool.

Suitably, the breath data includes breath cycle data, FEV, and/or peakflow data.

In one aspect, the coupling is exposable to the airflow arising from theinhalation or expiration of the patient to assist in the cooling of thecoupling post-actuation of the reset means. Other active coolingmechanisms may be employed, such as fan cooling.

Preferably the medicament dispenser comprises an actuation or dosecounter for counting the number of actuations of the reset means. Theactuation or dose counter may be mechanical or electronic. Morepreferably the actuation or dose counter is independent of the couplingso that counting will occur even if the reset means is manuallyactuated.

Suitably, the medicament dispenser additionally comprises an electronicdata management system. The electronic data management system hasinput/output capability and comprises a memory for storage of data; amicroprocessor for performing operations on said data; and a transmitterfor transmitting a signal relating to the data or the outcome of anoperation on the data.

Suitably, the electronic data management system comprises an electroniccontrol system for controlling the supply of energy to the coupling.Thus, in aspects the control system may regulate flow of electricalcurrent to the coupling or to any heater or electromagnet sourceassociated therewith.

The control system may form part of a larger electronic data managementsystem capable of receiving inputs from other electronic components. Inparticular, inputs may be received from any sensor to enable actuationof the coupling in response to sensor, particularly breath sensor input.

The control system may be arranged to accomplish any suitable control ofactuation of the coupling including varying the amount of energysupplied thereto, the rate of energy supplied thereto, pulsing patternsof energy supply to the coupling, and more complex control patterns.

Suitably, the electronic data management system is arranged to beresponsive to or activated by the voice of a user. Thus, for example thesystem may be switched on or off in response to a voice command.

The electronic data management system may be integral with the body.Alternatively, the electronic data management system forms part of abase unit which is reversibly associable with the body.

Suitably, the medicament dispenser additionally comprises a data inputsystem for user input of data to the electronic data management system.Preferably, the data input system comprises a man machine interface(MMI) preferably selected from a keypad, voice or noise recognitioninterface, graphical user interface (GUI) or biometrics interface.

Suitably, the system additionally comprises a visual display unit fordisplay of data from the electronic data management system to the user.The display may for example, comprise a screen such as an LED or LCDscreen. More preferably the visual display unit is associable with thehousing. More basic display units are envisaged also including those inwhich a light or pattern of lights is employed to act as a signal to thepatient.

The electronic data management system may further comprise a voicesynthesiser for verbal communication of data, instructions and feedbackto a user.

Suitably, the medicament dispenser additionally comprises a datalink forlinking to a local data store to enable communication of data betweenthe local data store and the electronic data management system. Thedatastore may also comprise data management, data analysis and datacommunication capability.

The datastore may itself form part of a portable device (e.g. a handhelddevice) or it may be sized and shaped to be accommodated within thepatient's home. The datastore may also comprise a physical storage areafor storage of replacement medicament containers. The datastore mayfurther comprise a system for refilling medicament from a reservoir ofmedicament product stored therewithin. The datastore may furthercomprise an electrical recharging system for recharging any electricalenergy store on the medicament dispenser, particularly a batteryrecharging system.

The datalink may for example enable linking with a docking station, apersonal computer, a network computer system or a set-top box by anysuitable method including a hard-wired link, an infra red link or anyother suitable wireless communications link.

Suitably, the medicament dispenser additionally comprises an actuationdetector for detecting actuation of the reset means wherein saidactuation detector transmits actuation data to the electronic datamanagement system.

The medicament dispenser may additionally comprise a safety mechanism toprevent unintended multiple actuations of the reset means. The patientis thereby protected from inadvertently receiving multiple doses ofmedicament in a situation where they take a number of short rapidbreaths. More preferably, the safety mechanism imposes a time delaybetween successive actuations of the reset means. The time delay istypically of the order of from three to thirty seconds.

Suitably, the medicament dispenser additionally comprises a releasedetector for detecting release of medicament from the medicamentcontainer, wherein said release detector transmits release data to theelectronic data management system.

Suitably, the medicament dispenser additionally comprises a shakedetector for detecting shaking of the medicament container (e.g. priorto actuation of the dispenser), wherein said shake detector transmitsshake data to the electronic data management system.

Suitably, the electronic data management system includes a predictivealgorithm or look-up table for calculating the optimum amount ofmedicament to dispense.

Suitably, the memory on the electronic data management system includes adose memory for storing dosage data and reference is made to the dosememory in calculating the optimum amount of medicament to dispense.

Suitably, the medicament dispenser additionally comprises a selector forselecting the amount of medicament to dispense from the dispenser. Inone aspect, the selector is manually operable. In another aspect, theselector is operable in response to a signal from the transmitter on theelectronic data management system.

Suitably, the medicament dispenser comprises in association with a bodyor housing thereof, a first transceiver for transmitting and receivingdata and in association with the medicament container, a secondtransceiver for transmitting and receiving data, wherein data istransferable in two-way fashion from the first transceiver to the secondtransceiver. The data is preferably in digital form and suitable fortransfer by electronic or optical means. A medicament dispenser of thisgeneral type is described in pending UK Patent Application No.0020538.5.

The body or housing of the medicament dispenser is typically shaped todefine a cavity within which the medicament container is receivable. Thebody and/or medicament container may be further shaped with any mannerof grooves, indentations or other shaping or surface details to define a‘lock and key’ relationship between the body and the container. Colourguides, arrows and any other surface markings may also be employed.

One advantage of embodiments of this type is the ability to store manytypes of information in different parts of the memory structure of thetransceivers. The information is furthermore stored in a form which isreadily and accurately transferable. The information could for example,include manufacturing and distribution compliance information written tothe memory at various points in the manufacturing or distributionprocess, thereby providing a detailed and readily accessible producthistory of the dispenser. Such product history information may, forexample, be referred to in the event of a product recall. The complianceinformation could, for example, include date and time stamps. Theinformation could also include a unique serial number stored inencrypted form or in a password protectable part of the memory whichuniquely identifies the product and therefore may assist in thedetection and prevention of counterfeiting. The information could alsoinclude basic product information such as the nature of the medicamentand dosing information, customer information such as the name of theintended customer, and distribution information such as the intendedproduct destination.

On loading or reloading the dispenser with a medicament container (suchas an aerosol canister or dry powder cassette) the second transceivermay, for example, read the unique serial number, batch code and expirydate of the medicament and any other information on the secondtransceiver. In this way the nature and concentration of the medicament,together with the number of doses used or remaining within thecontainer, may be determined. This information can be displayed to thepatient on a visual display unit. Other information, such as the numberof times the dispenser has been reloaded with a medicament container,may also be displayed.

Similarly, should the container be removed from the housing before thesupply of medicament is exhausted, the same data can be read from thesecond transceiver and the number of doses remaining or used determined.Other information, such as the date and time of administration of thedrug, or environmental exposure data such as the minimum/maximumtemperatures or levels of humidity the medicament container has beenexposed to, may also be read and displayed to the user.

In the event that the supply of medicament within the container becomesexhausted, or that the shelf life of the medicament has expired, or thatthe first transceiver does not recognise the batch code on the secondtransceiver, activation of the dispenser may be prevented to safeguardthe user. Activation may also be prevented if the medicament has beenexposed to extreme environmental conditions for periods outwith themanufacturer's guidelines.

Data may be transferred to and from any transceiver during the period ofuse of the medicament dispenser by the patient. For example, themedicament dispenser may include an electronic data management systemhaving various sensors associated therewith. Any data collected by thesensors or from any data collection system associated with theelectronic data management system including a clock or other date/timerecorder is transferable.

Data may be transferred each time the patient uses the device. Oralternatively, data may be stored in a database memory of the electronicdata management system and periodically downloaded to any transceiver.In either case, a history of the usage of the device may be built up inthe memory of a transceiver.

In one embodiment herein, a history of the usage of the medicamentdispenser is transferred to the second transceiver on the aerosolcontainer. When the medicament container is exhausted it is exchanged bythe patient for a new refill container. At the point of exchange, whichwill typically occur at the pharmacy, data may be transferred from theexhausted container to the refill and vice-versa. Additionally, usagehistory data may be read from the refill and transferred to a healthcaredata management system for example comprising a network computer systemunder the control of a healthcare data manager.

Methods are envisaged herein whereby the patient is given some sort ofreward for returning the refill and making available the data comprisedwithin the second transceiver. Methods are also envisaged herein wherebythe healthcare data manager is charged for either receipt of the datafrom the second transceiver or for its use for commercial purposes. Anyrewards or charging may be arranged electronically. The methods may beenabled by distributed or web-based computer network systems in whichany collected data is accessible through a hub on the network. The hubmay incorporate various security features to ensure patientconfidentiality and to allow selective access to information collecteddependent upon level of authorisation. The level of user authorisationmay be allocated primarily to safeguard patient confidentiality. Beyondthis the level of user authorisation may also be allocated on commercialterms with for example broader access to the database being authorisedin return for larger commercial payments.

Suitably, the first and second transceiver each comprise an antenna orequivalent for transmitting or receiving data and connecting thereto amemory. The memory will typically comprise an integrated circuit chip.Either transceiver may be configured to have a memory structure whichallows for large amounts of information to be stored thereon. The memorystructure can be arranged such that parts of the memory are read-only,being programmed during/after manufacture, other parts are read/writeand further parts are password protectable. Initial transfer ofinformation (e.g. on manufacture or one dispensing) to or from anytransceiver can be arranged to be readily achievable by the use of areader which is remote from the medical dispenser, thereby minimisingthe need for direct product handling. In further aspects, the reader canbe arranged to simultaneously read or write to the memory of multipletransceivers on multiple medicament dispensers.

A suitable power source such as a battery, clockwork energy store, solarcell, fuel cell or kinetics-driven cell will be provided as required toany electronic component herein. The power source may be arranged to berechargeable or reloadable.

Suitably, data is transferable in two-way fashion between the first andsecond transceiver without the need for direct physical contacttherebetween.

Preferably, data is transferable wirelessly between the first and secondtransceiver.

Suitably, the first transceiver is an active transceiver and the secondtransceiver is a passive transceiver. The term active is used to meandirectly powered and the term passive is used to mean indirectlypowered.

Suitably, the second transceiver comprises a label or tag comprising anantenna for transmitting or receiving energy; and an integrated circuitchip connecting with said antenna, and the first transceiver comprises areader for said label or tag. In this case the label or tag is a passivetransceiver and the reader is an active transceiver. Preferably, thereader will not need to be in direct contact with the tag or label toenable the tag or label to be read.

The tag may be used in combination and/or integrated with othertraditional product labelling methods including visual text,machine-readable text, bar codes and dot codes.

Suitably, the integrated circuit chip has a read only memory area, awrite only memory area, a read/write memory area or combinationsthereof.

Suitably, the integrated circuit chip has a one-time programmable memoryarea. More preferably, the one-time programmable memory area contains aunique serial number.

Suitably, the integrated circuit chip has a preset memory areacontaining a factory preset, non-changeable, unique data item. Thepreset memory item is most preferably in encrypted form.

Suitably, the integrated circuit chip has plural memory areas thereon.Suitably, any memory area is password protected.

Suitably, any memory area contains data in encrypted form. Electronicmethods of checking identity, error detection and data transfer may alsobe employed.

In one aspect, the integrated circuit has plural memory areas thereonincluding a read only memory area containing a unique serial number,which may for example be embedded at the time of manufacture; aread/write memory area which can be made read only once information hasbeen written thereto; and a password protected memory area containingdata in encrypted form which data may be of anti-counterfeiting utility.

Suitably, the tag is on a carrier and the carrier is mountable on thebody or housing of the medicament dispenser or the medicament container.

In one aspect, the carrier is a flexible label. In another aspect, thecarrier is a rigid disc. In a further aspect, the carrier is arectangular block. In a further aspect, the carrier is a collar ringsuitable for mounting to the neck of an aerosol container. Other shapesof carrier are also envisaged.

Suitably, the carrier is mouldable or weldable to the medicamentcontainer or housing. Suitably, the carrier encases the tag. Morepreferably, the carrier forms a hermetic seal for the tag.

In one aspect, the carrier comprises an insulating material such as aglass material or, a paper material or an organic polymeric materialsuch as polypropylene. Alternatively, the carrier comprises a ferritematerial.

The energy may be in any suitable form including ultrasonic, infrared,radiofrequency, magnetic, optical and laser form. Any suitable channelsmay be used to channel the energy including fibre optic channels.

In one aspect, the second transceiver comprises a radiofrequencyidentifier comprising an antenna for transmitting or receivingradiofrequency energy; and an integrated circuit chip connecting withsaid antenna, and the first transceiver comprises a reader for saidradiofrequency identifier. In this case the radiofrequency identifier isa passive transceiver and the reader is an active transceiver. Anadvantage of radiofrequency identifier technology is that the readerneed not be in direct contact with the radiofrequency identifier tag orlabel to be read.

The radiofrequency identifier can be any known radiofrequencyidentifier. Such identifiers are sometimes known as radiofrequencytransponders or radiofrequency identification (RFID) tags or labels.Suitable radiofrequency identifiers include those sold by PhillipsSemiconductors of the Netherlands under the trade marks Hitag and Icode,those sold by Amtech Systems Corporation of the United States of Americaunder the trade mark Intellitag, and those sold by Texas Instruments ofthe United States of America under the trade mark Tagit.

Suitably, the antenna of the RFID tag is capable of transmitting orreceiving radiofrequency energy having a frequency of from 100 KHz to2.5 GHz. Preferred operating frequencies are selected from 125 KHz,13.56 MHz and 2.4 GHz.

In one aspect, the second transceiver comprises a magnetic label or tagcomprising an antenna for transmitting or receiving magnetic fieldenergy; and an integrated circuit chip connecting with said antenna, andthe first transceiver comprises a reader for said magnetic label or tag.In this case the magnetic label or tag is a passive transceiver and thereader is an active transceiver.

A suitable magnetic label or tag comprises plural magnetic elements inmutual association whereby the magnetic elements move relative to eachother in response to an interrogating magnetic field. A magnetic labelor tag of this type is described in U.S. Pat. No. 4,940,966. Anothersuitable magnetic label or tag comprises a magnetorestrictive elementwhich is readable by application of an interrogating alternatingmagnetic field in the presence of a magnetic bias field which results inresonance of the magnetorestrictive elements at different predeterminedfrequencies. A magnetic label of this type is described in PCT PatentApplication No. WO92/12402. Another suitable magnetic label or tagcomprising plural discrete magnetically active regions in a linear arrayis described in PCT Patent Application No. WO96/31790. Suitable magneticlabels and tags include those making use of Programmable MagneticResonance (PMR) (trade name) technology.

In another aspect, the second transceiver comprises a microelectronicmemory chip and the first transceiver comprises a reader for saidmicroelectronic memory chip. The microelectronic memory chip maycomprise an Electrically Erasable Programmable Read Only Memory (EEPROM)chip or a SIM card-type memory chip. In this case the microelectronicmemory chip is a passive transceiver and the reader is an activetransceiver.

Any transceiver herein, particularly a passive transceiver may bemounted on or encased within any suitable inert carrier. The carrier maycomprise a flexible sheet which may in embodiments be capable ofreceiving printed text thereon.

In one aspect, the first transceiver is integral with the body such thata single unit is comprised. The first transceiver may for example beencased within or moulded to the body.

In another aspect, the first transceiver forms part of a base unit whichis reversibly associable with the body. The base unit may for example,form a module receivable by the body such as a snap-in module.

Suitably, the medicament dispenser additionally comprises a communicatorfor wireless communication with a network computer system to enabletransfer of data between the network computer system and the electronicdata management system. Dispensers employing such communicators aredescribed in pending PCT Applications No.s PCT/EP00/09291 (PG3786),PCT/EP00/09293 (PG4029) and PCT/EP00/09292 (PG4159). Preferably, thecommunicator enables two-way transfer of data between the networkcomputer system and the electronic data management system.

Suitably, the data is communicable between the network computer systemand the electronic data management system in encrypted form. Allsuitable methods of encryption or partial encryption are envisaged.Password protection may also be employed. Suitably, the communicatoremploys radiofrequency or optical signals.

In one aspect, the communicator communicates via a gateway to thenetwork computer system. In another aspect, the communicator includes anetwork server (e.g. a web server) such that it may directly communicatewith the network.

In a further aspect, the communicator communicates with the gateway viaa second communications device. Preferably, the second communicationsdevice is a telecommunications device, more preferably a cellular phoneor pager. Preferably, the communicator communicates with the secondcommunications device using spread spectrum radiofrequency signals. Asuitable spread spectrum protocol is the Bluetooth (trade mark) standardwhich employs rapid (e.g. 1600 times a second) hopping between pluralfrequencies (e.g. 79 different frequencies). The protocol may furtheremploy multiple sending of data bits (e.g. sending in triplicate) toreduce interference.

In one aspect, the network computer system comprises a public accessnetwork computer system. The Internet is one suitable example of apublic access network computer system, wherein the point of accessthereto can be any suitable entrypoint including an entrypoint managedby an Internet service provider. The public access network computersystem may also form part of a telecommunications system, which mayitself be either a traditional copper wire system, a cellular system oran optical network.

In another aspect, the network computer system comprises a privateaccess network computer system. The private access network system mayfor example, compnse an Intranet or Extranet which may for example, bemaintained by a health service provider or medicament manufacturer. Thenetwork may for example include password protection; a firewall; andsuitable encryption means.

Preferably, the communicator enables communication with a user-specificnetwork address in the network computer system.

The user-specific network address may be selected from the groupconsisting of a web-site address, an e-mail address and a file transferprotocol address. Preferably, the user-specific network address isaccessible to a remote information source such that information fromsaid remote information source can be made available thereto. Morepreferably, information from the user-specific network address can bemade available to the remote information source.

In one aspect, the remote information source is a medicament prescriber,for example a doctor's practice. Information transferred from themedicament prescriber may thus, comprise changes to prescriptiondetails, automatic prescription updates or training information.Information transferred to the medicament prescriber may comprisecompliance information, that is to say information relating to thepatient's compliance with a set prescribing programme. Patientperformance information relating for example, to patient-collecteddiagnostic data may also be transferred to the medicament prescriber.Where the dispenser is an inhaler for dispensing medicament for therelief of respiratory disorders examples of such diagnostic data wouldinclude breath cycle data or peak flow data.

In another aspect, the remote information source is a pharmacy.Information transferred from the pharmacy may thus, comprise informationrelating to the medicament product. Information sent to the pharmacy maythus include prescription requests which have been remotelypre-authorised by the medicament prescriber.

In a further aspect, the remote information source is an emergencyassistance provider, for example a hospital accident and emergencyservice or an emergency helpline or switchboard. The information maythus, comprise a distress or emergency assist signal which requestsemergency assistance.

In a further aspect, the remote information source is a manufacturer ofmedicament or medicament delivery systems. Information transferred tothe system may thus, comprise product update information. The system mayalso be configured to feed information back to the manufacturer relatingto system performance.

In a further aspect, the remote information source is a researchestablishment. In a clinical trial situation, information may thus betransferred relating to the trial protocol and information relating topatient compliance fed back to the research establishment.

In a further aspect, the remote information source is an environmentalmonitoring station. Information relating to weather, pollen counts andpollution levels may thus be made accessible to the system.

In a further aspect, the remote information source is a computersoftware download site from which software may be downloaded for use inthe electronic data management system. Embodiments are envisaged inwhich such software downloads are employed to upgrade or modify anyexisting software employed by the electronic data management system.

Suitably, the medicament dispenser additionally comprises a geographicpositioning system such as a global positioning system or a system whichrelies on the use of multiple communications signals and a triangulationalgorithm.

In another embodiment, the inhaler additionally comprises climatecontrol means. Preferably, the climate control means is actuable by thecoupling.

The climate control means may comprise means to (i) reduce moistureincrease in the dispenser; and/or (ii) maintain ambient temperature;and/or (iii) dry the meter prior to actuation of the dispenser.

The climate control means may comprise a desiccant and/or a heater.

The climate control means may comprise a temperature and/or a moisturesensor.

The dispenser of the invention is suitable for dispensing medicament,particularly for the treatment of respiratory disorders such as asthmaand chronic obstructive pulmonary disease (COPD).

Appropriate medicaments may thus be selected from, for example,analgesics, e.g., codeine, dihydromorphine, ergotamine, fentanyl ormorphine; anginal preparations, e.g., diltiazem; antiallergics, e.g.,cromoglycate, ketotifen or nedocromil; antiinfectives e.g.,cephalosporins, penicillins, streptomycin, sulphonamides, tetracyclinesand pentamidine; antihistamines, e.g., methapyrilene;anti-inflammatories, e.g., beclomethasone dipropionate, fluticasonepropionate, flunisolide, budesonide, rofleponide, mometasone furoate ortriamcinolone acetonide; antitussives, e.g., noscapine; bronchodilators,e.g., albuterol, saimeterol, ephedrine, adrenaline, fenoterol,formoterol, isoprenaline, metaproterenol, phenylephrine,phenylpropanolamine, pirbuterol, reproterol, rimiterol, terbutaline,isoetharine, tulobuterol, or(−)-4-amino-3,5-dichloro-α-[[[6-[2-(2-pyridinyl)ethoxy] hexyl]methyl]benzenemethanol; diuretics, e.g., amiloride; anticholinergics, e.g.,ipratropium, tiotropium, atropine or oxitropium; hormones, e.g.,cortisone, hydrocortisone or prednisolone; xanthines, e.g.,aminophylline, choline theophyllinate, lysine theophyllinate ortheophylline; therapeutic proteins and peptides, e.g., insulin orglucagon. It will be clear to a person skilled in the art that, whereappropriate, the medicaments may be used in the form of salts, (e.g., asalkali metal or amine salts or as acid addition salts) or as esters(e.g., lower alkyl esters) or as solvates (e.g., hydrates) to optimisethe activity and/or stability of the medicament.

Medicaments can also be delivered in combinations. Preferredformulations containing combinations of active ingredients containsalbutamol (e.g., as the free base or the sulphate salt) or salmeterol(e.g., as the xinafoate salt) in combination with an antiinflammatorysteroid such as a beclomethasone ester (e.g., the dipropionate) or afluticasone ester (e.g., the propionate). A particularly preferredcombination comprises salmeterol xinafoate salt and fluticasonepropionate.

Preferred medicaments are selected from albuterol, salmeterol,fluticasone propionate and beclomethasone dipropionate and salts orsolvates thereof, e.g., the sulphate of albuterol and the xinafoate ofsalmeterol, and any mixtures thereof. Alternatively, the dispenser maybe employed for dispensing vaccine.

The medicament container may comprise medicament in dry powder form.Typically, a dry powder medicament includes a pharmaceutical excipientin dry powder form.

In one embodiment, the density of the dry powder medicament particles isreduced relative to standard dry powder medicament.

In another embodiment, the dry powder medicament particles areaerodynamically shaped to improve medicament delivery to the patient.

In another embodiment, the medicament container may comprise medicamentin solution or suspension form.

The medicament container may comprise a suspension of a medicament in apropellant, for example, liquefied HFA134a, HFA-227, helium or carbondioxide.

Alternatively, the medicament container may comprise a solution of amedicament in a solvent.

Preferably, the medicament dispenser additionally comprises a safetymechanism to prevent unintended multiple actuations of the reset means.

The safety mechanism may impose a time delay between successiveactuations of the reset means.

Preferably, the medicament dispenser comprises a manual overrideenabling manual actuation of the reset means. The manual override may bedesigned to cover all situations in which the coupling does not actuatein the normal manner. These will include situations where actuation doesnot happen (e.g. due to power failure). Alternatively, this will includesituations where actuation occurs, but reset of the coupling fails (e.g.due to power being in “continuous on” mode) and a manual reset,decoupling (e.g. by severing the coupling) or “circuit break” isemployed.

Preferably, the medicament dispenser comprises a child resistancefeature to prevent undesirable actuation thereof by children.

In another aspect, the invention provides an actuator for use in amedicament dispenser as described hereinabove.

In a further aspect, the invention provides an actuator for a medicamentcontainer comprising a housing, within said housing, a container seatfor receipt of the medicament container; on the housing or connectingtherewith, reset means to reset a mechanical mechanism, wherein thereset means comprises a reset coupling which is reversibly deformable inresponse to the application of non-mechanical energy thereto.

The actuator herein may be configured to include, as relevant, any ofthe above described features of the medicament dispenser. In particular,the actuator may be configured to include an electronic data managementsystem comprising control means for the actuation of the coupling.

Preferably, the non-mechanical energy comprises electric current flowthrough the coupling.

In one embodiment, the coupling comprises one or more wires whichcontract in response to application of non-mechanical energy thereto.More preferably, the one or more wires comprise an alloy which undergoesa phase transition on heating, for example in response to flow ofelectrical current therethrough. The alloy is for example, anickel-titanium alloy.

In another embodiment, the one or more wires comprise an alloy whichundergoes a phase transition on application of a magnetic field thereto(magnetic shape memory alloys).

Suitably, the actuator additionally comprises an electronic controlsystem for controlling the supply of non-mechanical energy to thecoupling. Suitably, the electronic control system is capable ofproviding pulses of non-mechanical energy to the coupling.

Suitably, the electronic control system is capable of receiving inputsfrom electronic sensors locatable on the dispenser. Suitably, theactuator additionally comprises an electronic sensor selected from thegroup consisting of a breath sensor, a shake sensor, a temperaturesensor, an infrared sensor and a patient ID sensor.

In a further aspect, the invention provides a medicament container foruse in the dispenser and/or the actuator as described hereinabove.

According to a further aspect of the present invention there is provideda laboratory test apparatus comprising at least one actuator asdescribed above and a mounting (e.g. a bench mounting) for the at leastone actuator. The laboratory test apparatus is designed for use intesting the performance of the medicament dispenser in a laboratoryenvironment. Often, plural actuators will be mounted on a singlemounting to enable simultaneous testing thereof. The laboratory testapparatus will typically be connected to various sensors and recordingdevices for monitoring aspects of the performance of the medicamentdispenser.

According to a further aspect of the present invention there is provideda kit of parts comprising a medicament dispenser as described above inthe form of a cartridge; and a housing shaped for receipt of saidcartridge.

According to a further aspect of the present invention there is provideda kit of parts comprising an actuator as described above and, receivableby said actuator, a medicament container.

In a preferred commercial embodiment herein, the actuator is arrangedfor receipt of a refill cartridge. Typically, the actuator is in theform of a relatively complex device, including for example an electronicdata management system and the cartridge is in the form of a medicamentrefill therefor.

In another aspect the cartridge comprises a medicament dispenser havinga voltaic cell as an electrical energy source and the housing isprovided with a mouthpiece for patient inhalation therethrough andelectronic information display apparatus for displaying information tothe patient.

The invention will now be described further with reference to theaccompanying figures in which:

FIG. 1 a shows an inhaler in accordance with one embodiment of theinvention in a rest position;

FIG. 1 b shows the inhaler of FIG. 1 a in a primed position;

FIG. 1 c shows the inhaler of FIGS. 1 a and 1 b in a firing position;and

FIG. 1 d shows the inhaler of FIGS. 1 a to 1 c whilst resetting viareset means.

Referring now to the figures, FIGS. 1 a to d schematically represent abreath operated metered dose inhaler 2. The inhaler comprises a canister4 containing a suspension of medicament in a pressurised propellant suchas p134a. The canister is linked at it base to a valve 6. Relativemovement of the canister 4 with respect to the valve 6 results in ametered dose of medicament being dispensed to the patient. A mouthpiece8 protrudes from the inhaler for passage of the medicament to thepatient.

At rest (as shown in FIG. 1 a) the canister 4 is retained in anon-dispensing position by a firing lever 10 pivotally mounted atfulcrum 12 and locked in position by firing cam lock 16. Firing lever 10is pivotally linked at 18 to a tension spring 20 which is connected to apriming lever 22 and pivotally linked at its other end 24 to thecanister 4. The tension spring 20 acts as an energy store for actuatingthe firing mechanism of the inhaler as described infra.

To prime the device for dispensing a patient depresses the priming lever22 (see FIG. 1 b). This induces a tension in the tension spring 20 asthe spring is extended. The priming lever 22 is locked into the primingposition by priming cam lock 26.

As the patient inhales, a breath sensor (not shown) registers thepatient's breath, completes an electrical circuit (not shown), thecurrent from which heats a trigger coupling or in this case, a firingshape memory alloy (SMA) wire 28 which is linked to the firing cam lock16. As the SMA wire 28 increases in temperature it contracts, and indoing so removes the firing cam lock 16 from the firing lever 10. Thetension spring 20 now releases its energy and recoils upwards and pivotsthe firing lever 10 downwards thus pulling the canister 4 down relativeto the valve 6 to release a dose of medicament through the mouthpiece 8of the inhaler.

A reset means is shown in FIG. 1 d. The advantages of having a positivereset mechanism are numerous. In devices where there is no resetmechanism it is possible for the canister to stick in the firingposition. This may effect the efficacy of further inhaler actuations aswell as dosing efficacy and can result in medicament leakage.Furthermore, the longer the canister remains in the firing position, theincreased likelihood of medicament deposition and/or increasedmedicament concentration in the lower parts of the canister. A positivereset mechanism is therefore technically advantageous in addition toincreasing consumer confidence and ease of use of the device.

There may be either a separate reset button linked to the reset means orthe reset means may be actuated after a predetermined time delay postfiring of the inhaler. Once actuated, a reset SMA wire 30 heats andcontracts pulling a reset cam lock 32 down and releasing the priminglever 22. As the priming lever 22 returns to its rest position asillustrated in FIG. 1 a, the firing lever 10 is returned to its restposition via the tension spring 20. The firing lever 10 is then relockedin its rest position by the firing cam lock 16.

It may be appreciated that any of the parts of the inhaler or actuatorwhich contact the medicament suspension may be coated with materialssuch as fluoropolymer materials which reduce the tendency of medicamentto adhere thereto. Any movable parts may also have coatings appliedthereto which enhance their desired movement characteristics. Frictionalcoatings may therefore be applied to enhance frictional contact andlubricants used to reduce frictional contact as necessary.

It will be understood that the present disclosure is for the purpose ofillustration only and the invention extends to modifications, variationsand improvements thereto.

The application of which this description and claims form part may beused as a basis for priority in respect of any subsequent application.The claims of such subsequent application may be directed to any featureor combination of features described therein. They may take the form ofproduct, method or use claims and may include, by way of example andwithout limitation, one or more of the following claims:

1. A medicament dispenser comprising a body, a medicament containerhaving a dose-liberating means for liberating a dose of medicament fromthe container, a mechanical mechanism actuable to cause thedose-liberating means to liberate a dose of medicament from thecontainer, and reset means for resetting the mechanical mechanism afteractuation thereof, wherein the reset means comprises a reset couplingcomprising at least one wire, strip, coil or tube which is reversiblycontractible in response to electrical current flow therethrough.
 2. Amedicament dispenser according to claim 1 wherein the mechanicalmechanism is a trigger means.
 3. A medicament dispenser according toclaim 1 wherein the dose-liberating means takes the form of a valve. 4.A medicament dispenser according to claim 1, wherein the couplingcomprises multiple wires, strips, coils or tubes.
 5. A medicamentdispenser according to claim 1, wherein the coupling comprises one ormore wires which contract in response to electrical current flowtherethrough.
 6. A medicament dispenser according to claim 5, whereinthe one or more wires exhibit(s) a degree of contraction of from 2% to8% on electrical current flow therethrough.
 7. A medicament dispenseraccording to claim 6, wherein the one or more wires comprise(s) an alloywhich undergoes a phase transition on electrical current flowtherethrough.
 8. A medicament dispenser according to claim 7, whereinsaid alloy is a nickel-titanium alloy.
 9. A medicament dispenseraccording to claim 8, wherein said nickel-titanium alloy comprises from5% to 95% nickel by weight and from 95% to 5% titanium by weight.
 10. Amedicament dispenser according to claim 8, wherein said nickel-titaniumalloy additionally comprises copper, niobium or any mixtures thereof.11. A medicament dispenser according to claim 7, wherein the alloy is acopper-zinc-aluminium alloy or a copper-aluminium-nickel alloy.
 12. Amedicament dispenser according to claim 7, wherein the alloy has thecomposition defined as Ni_(65-x-y)Mn₂₀+xGa₁₅+y, where x is between 3atomic % and 15 atomic % and y is between 3 atomic % and 12 atomic %.13. A medicament dispenser according to claim 7, wherein the alloy hasthe composition defined as(Ni_(a)Fe_(b)Co_(c))_(65-x-y)(Mn_(d)Fe_(e)Co_(f))₂₀+x(Ga_(g)Si_(h)Al_(i))₁₅+y,where x is between 3 atomic % and 15 atomic % and y is between 3 atomic% and 12 atomic %, and where a+b+c=1, where d+e+f=1, and g+h+i=1.
 14. Amedicament dispenser according to claim 7, wherein the alloy comprisesan ion-exchange polymer composite.
 15. A medicament dispenser accordingto claim 7, wherein the alloy comprises a contractile polymer.
 16. Amedicament dispenser according to claim 5, wherein said one or morewires have a diameter from 30 to 400 micrometers.
 17. A medicamentdispenser according to claim 1, wherein the coupling is contractible inresponse to heating arising from electrical current flow in the rangefrom 100A to 0.01A.
 18. A medicament dispenser according to claim 1,additionally comprising an electrical energy source.
 19. A medicamentdispenser according to claim 1, in the form of an inhaler for thedelivery of inhalable medicament.
 20. A medicament dispenser accordingto claim 19, wherein heating arising from flow of electrical currentthrough the coupling and hence, actuation of the reset means isresponsive to a patient-actuable mechanism comprising a sensor whichsenses the breath of a patient.
 21. A medicament dispenser according toclaim 1 wherein the medicament container comprises medicament insolution or suspension form.
 22. A medicament dispenser according toclaim 21 wherein the medicament container comprises a suspension of amedicament in a propellant.
 23. A medicament dispenser according toclaim 21 wherein the medicament container comprises a solution of amedicament in a solvent.